A highly thermally stable sub-20 nm magnetic random-access memory based on perpendicular shape anisotropy.
A new approach to increase the downsize scalability of perpendicular STT-MRAM is presented. It consists of significantly increasing the thickness of the storage layer in out-of-plane magnetized tunnel junctions (pMTJ) as compared to conventional pMTJ in order to induce a perpendicular shape anisotropy (PSA) in this layer. This PSA is obtained by depositing a thick ferromagnetic (FM) layer on top of an MgO/FeCoB based magnetic tunnel junction (MTJ) so that the thickness of the storage layer is of the order of or larger than the diameter of the MTJ pillar. In contrast to conventional spin transfer torque magnetic random access memory (STT-MRAM) wherein the demagnetizing energy opposes the interfacial perpendicular magnetic anisotropy (iPMA), in these novel memory cells, both PSA and iPMA contributions favor the out-of-plane orientation of the storage layer magnetization. Using thicker storage layers in these PSA-STT-MRAMs has several advantages. Due to the PSA, very high and easily tunable thermal stability factors can be achieved, even down to sub-10 nm diameters. Moreover, a low damping material can be used for the thick FM material thus leading to a reduction of the write current. The paper describes this new PSA-STT-MRAM concept, practical realization of such memory arrays, magnetic characterization demonstrating thermal stability factor above 200 for MTJs as small as 8 nm in diameter and possibility to maintain the thermal stability factor above 60 down to 4 nm diameter.


Sequence variation in the CHAT locus shows no association with late-onset Alzheimer's disease.
There is substantial evidence for a susceptibility gene for late-onset Alzheimer's disease (AD) on chromosome 10. One of the characteristic features of AD is the degeneration and dysfunction of the cholinergic system. The genes encoding choline acetyltransferase (ChAT) and its vesicular transporter (VAChT), CHAT and SLC18A3 respectively, map to the linked region of chromosome 10 and are therefore both positional and obvious functional candidate genes for late-onset AD. We have screened both genes for sequence variants and investigated each for association with late-onset AD in up to 500 late-onset AD cases and 500 control DNAs collected in the UK. We detected a total of 17 sequence variants. Of these, 14 were in CHAT, comprising three non-synonymous variants (D7N in the S exon, A120T in exon 5 and L243F in exon 8), one synonymous change (H547H), nine single-nucleotide polymorphisms in intronic, untranslated or promoter regions, and a variable number of tandem repeats in intron 7. Three non-coding SNPs were detected in SLC18A3. None demonstrated any reproducible association with late-onset AD in our samples. Levels of linkage disequilibrium were generally low across the CHAT locus but two of the coding variants, D7N and A120T, proved to be in complete linkage disequilibrium.


Real-time iterative monitoring of radiofrequency ablation tumor therapy with 15O-water PET imaging.
A method that provides real-time image-based monitoring of solid tumor therapy to ensure complete tumor eradication during image-guided interventional therapy would be a valuable tool. The short, 2-min half-life of (15)O makes it possible to perform repeated PET imaging at 20-min intervals at multiple time points before and after image-guided therapy. In this study, (15)O-water PET was evaluated as a tool to provide real-time feedback and iterative image guidance to rapidly monitor the intratumoral coverage of radiofrequency (RF) ablation therapy. Tumor RF ablation therapy was performed on head and neck squamous cell carcinoma (SCC) xenograft tumors (length, approximately 23 mm) in 6 nude rats. The tumor in each animal was ablated with RF (1-cm active size ablation catheter, 70 degrees C for 5 min) twice in 2 separate tumor regions with a 20-min separation. The (15)O-water PET images were acquired before RF ablation and after the first RF and second RF ablations using a small-animal PET scanner. In each PET session, approximately 100 MBq of (15)O-water in 1.0 mL of saline were injected intravenously into each animal. List-mode PET images were acquired for 7 min starting 20 s before injection. PET images were reconstructed by 2-dimensional ordered-subset expectation maximization into single-frame images and dynamic images at 10 s/frame. PET images were displayed and analyzed with software. Pre-RF ablation images demonstrate that (15)O-water accumulates in tumors with (15)O activity reaching peak levels immediately after administration. After RF ablation, the ablated region had almost zero activity, whereas the unablated tumor tissue continued to have a high (15)O-water accumulation. Using image feedback, the RF probe was repositioned to a tumor region with residual (15)O-water uptake and then ablated. The second RF ablation in this new region of the tumor resulted in additional ablation of the solid tumor, with a corresponding decrease in activity on the (15)O-water PET image. (15)O-water PET clearly demonstrated the ablated tumor region, whereas the unablated tumor continued to show high (15)O-water accumulation. (15)O-water imaging shows promise as a tool for on-site, real-time monitoring of image-guided interventional cancer therapy.


Novel nanostructured Fe-Cu-Al trimetal oxide for enhanced antimony(V) removal: synthesis, characterization and performance.
Given the adverse health effects of antimony (Sb), there is an increased focus on developing methods to remove this toxic metal from contaminated water bodies. To effectively remove Sb(V), a new nanostructured Fe-Cu-Al trimetal oxide was fabricated using co-precipitation method at ambient temperature. The Fe-Cu-Al trimetal oxide was very effective at removing Sb(V) from water; it had a maximal adsorption capacity of 169.1 mg/g at pH 7.0, a capacity that was competitive with most other reported adsorbents. The obtained amorphous oxide had a high pH point of zero charge (pHpzc = 8.8) and good adsorption Sb(V) efficiency over a wide pH range (4.0-8.0). Sb(V) uptake was achieved mainly through an ion-exchange reaction between Sb(V) ions and hydroxyl groups on the surface of the oxide. Given its good removal performance, high selectivity, and simple synthesis, this novel Fe-Cu-Al trimetal oxide offers a promising alternate for removing antimony contamination from aquatic environments.


Clinical and Practice Variations in Pediatric Acute Recurrent or Chronic Pancreatitis: Report From the INSPPIRE Study.
The aim of the study was to determine whether clinical characteristics and management of pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) differ across INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In Search for a cuRE) sites. Data were collected from INSPPIRE and analyzed per US regions and "non-US" sites. Between-group differences were compared by Pearson chi-square test. Differences in disease burden were compared by Kruskal-Wallis test. Out of the 479 subjects, 121 (25%) were enrolled in West, 151 (32%) Midwest, 45 Northeast (9%), 78 (16%) South, and 84 (18%) at non-US sites. Hispanic ethnicity was more common in South (P < 0.0001); white race in Northeast (P = 0.009). CP was less common and time from diagnosis of first acute pancreatitis to CP was longer in children at non-US sites (P = 0.0002 and P = 0.011, respectively). Genetic mutations were most common among all groups; PRSS1 variants predominated in Midwest (P = 0.002). Gallstones were more frequent in South (P = 0.002). Endoscopic retrograde cholangiopancreatography (ERCP) and computed tomography (CT) imaging were more commonly utilized in United States compared with non-United States (P < 0.0001), but there were no differences in the use of MRI/MRCP. Disease burden was highest in the West and Midwest, possibly as total pancreatectomy and islet autotransplantation (TPIAT) referral sites were located in these regions. All therapies were less commonly administered in non-US sites (P < 0.0001). This is the first study to describe geographical variations in the INSPPIRE cohort, which possibly reflect variations in practice and referral patterns. The underlying reason behind the lower frequency of CP and fewer treatments in non-United States sites need to be further explored.


Axial compartmentation of descending and ascending thin limbs of Henle's loops.
In the inner medulla, radial organization of nephrons and blood vessels around collecting duct (CD) clusters leads to two lateral interstitial regions and preferential intersegmental fluid and solute flows. As the descending (DTLs) and ascending thin limbs (ATLs) pass through these regions, their transepithelial fluid and solute flows are influenced by variable transepithelial solute gradients and structure-to-structure interactions. The goal of this study was to quantify structure-to-structure interactions, so as to better understand compartmentation and flows of transepithelial water, NaCl, and urea and generation of the axial osmotic gradient. To accomplish this, we determined lateral distances of AQP1-positive and AQP1-negative DTLs and ATLs from their nearest CDs, so as to gauge interactions with intercluster and intracluster lateral regions and interactions with interstitial nodal spaces (INSs). DTLs express reduced AQP1 and low transepithelial water permeability along their deepest segments. Deep AQP1-null segments, prebend segments, and ATLs lie equally near to CDs. Prebend segments and ATLs abut CDs and INSs throughout much of their descent and ascent, respectively; however, the distal 30% of ATLs of the longest loops lie distant from CDs as they approach the outer medullary boundary and have minimal interaction with INSs. These relationships occur regardless of loop length. Finally, we show that ascending vasa recta separate intercluster AQP1-positive DTLs from descending vasa recta, thereby minimizing dilution of gradients that drive solute secretion. We hypothesize that DTLs and ATLs enter and exit CD clusters in an orchestrated fashion that is important for generation of the corticopapillary solute gradient by minimizing NaCl and urea loss.


Assessment of interplay between UV wavelengths, material surfaces and food residues in open surface hygiene validation.
The use of UV-visible radiation for detecting invisible residue on different surfaces as a means of validating cleanliness was investigated. Wavelengths at 365, 395, 435, 445, 470 and 490 nm from a monochromator were used to detect residues of beef, chicken, apple, mango and skim milk. These were on three surfaces: aluminium, fibre re-enforced plastic (FRP; Q-Liner®) and stainless steel, pre- and post a cleaning step using commercial detergent. The area covered by residues as detected by specific wavelengths was compared statistically. The sensitivity of the wavelengths for detection differed significantly (p < 0.05) for various residues depending on the material surfaces. Generally, wavelengths 365-445 nm were consistently able to illuminate all residue before cleaning, though sensitivity varied, while 490 nm showed more of the surface structural features instead of residue. The 365-395 nm wavelengths were significantly more sensitive (p < 0.05) for detecting beef and chicken residues on aluminium and stainless steel both before and after cleaning. The 435-445 nm wavelengths were significantly more sensitive for detecting apple and mango residues on the FRP both before and after cleaning. It is important when UV-systems are used as real-time tools for assessing cleanliness of surfaces that the surface materials being illuminated are taken into account in the choice of lamp wavelength, in addition to expected residue. This will ensure higher confidence in results during the use of UV-light for real-time hygiene validation of surfaces.


NETosis contributes to the pathogenesis of diabetes and its complications.
NETosis, a novel form of neutrophil-related cell death, acts as a major regulator of diabetes and diabetes-associated complications. In this review, we show that the extrusion of neutrophil extracellular traps, termed NETs, plays an important role in the pathogenesis of type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and diabetes-induced complications. In T1DM, β-cell death induces the sequestration of neutrophils in the pancreas and seems to be correlated with increased NETosis. In T2DM patients, products of NETs release are significantly elevated. Increased levels of dsDNA are correlated with the presence of cardiovascular disease and diabetic kidney disease, further supporting the role of NETosis in the pathogenesis of other diabetes-induced complications such as impaired wound healing and diabetic retinopathy. NETosis is induced by high glucose through incompletely understood mechanisms, but it also appears to be elevated in patients with diabetes who have tightly controlled glucose levels. We hypothesize that hyperglycemia worsens the already elevated baseline of NETosis in diabetic patients to further increase its detrimental effects.


Mechanical devices for urinary incontinence in women.
Incontinence can have a devastating effect on the lives of sufferers with significant economic implications. Non-surgical treatments such as pelvic floor muscle training and the use of mechanical devices are usually the first line of management, particularly when a woman does not want surgery or when she is considered unfit for surgery. Mechanical devices are inexpensive and do not compromise future surgical treatment. To determine whether mechanical devices are useful in the management of adult female urinary incontinence. For this second update we searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE in process, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings (searched 21 August 2014), EMBASE (January 1947 to 2014 Week 34), CINAHL (January 1982 to 25 August 2014), and the reference lists of relevant articles. All randomised or quasi-randomised controlled trials of mechanical devices in the management of adult female urinary incontinence determined by symptom, sign or urodynamic diagnosis. The reviewers assessed the identified studies for eligibility and risk of bias and independently extracted data from the included studies. Data analysis was performed using RevMan software (version 5.3). One new trial was identified and included in this update bringing the total to eight trials involving 787 women. Three small trials compared a mechanical device with no treatment and although they suggested that use of a mechanical device might be better than no treatment, the evidence for this was inconclusive. Four trials compared one mechanical device with another. Quantitative synthesis of data from these trials was not possible because different mechanical devices were compared in each trial using different outcome measures. Data from the individual trials showed no clear difference between devices, but with wide confidence intervals. One trial compared three groups: a mechanical device alone, behavioural therapy (pelvic floor muscle training) alone and behavioural therapy combined with a mechanical device. While at three months there were more withdrawals from the device-only group, at 12 months differences between the groups were not sustained on any measure. The place of mechanical devices in the management of urinary incontinence remains in question. Currently there is little evidence from controlled trials on which to judge whether their use is better than no treatment and large well-conducted trials are required for clarification. There was also insufficient evidence in favour of one device over another and little evidence to compare mechanical devices with other forms of treatment.


Performances of a polymer-cholesteric-liquidcrystal output-coupler in Nd-doped fiber lasers.
The performances and characteristics of a polymer-cholestericliquid-crystal reflector, used as an output coupler in a Nd-doped fiber laser, are presented. We show that a judicious combination of a linear polarizer and a quarter wave plate with the cholesteric coupler allows for a continuous scanning of the output-intensity from zero to a maximum value following the well-known Malus law. The results are shown to be contained in a simple Jones Matrix formalism. The LP-QW-PCLC combination is characterized by a reflection coefficient that can be freely adjusted from 0 to 1 by a simple rotation of the quarter-wave plate.


Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study.
Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4-5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment. Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1-14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5-86·6) of 107 patients. The most common grade 3-4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related). Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. AbbVie and Genentech.


[Preliminary results in a placebo-controlled, double-blind crossover clinical trial with human interleukin-2 (n-IL-2) in patients with variable immunodeficiency syndrome (CVID)].
Ten CVID patients with an in vitro defect for IL-2-synthesis were treated for 12 months in a placebo-controlled double-blind crossover therapy study with human natural IL-2 s.c. There were no severe side effects of n-IL-2 recorded. Serum levels of soluble IL-2 receptors were unaffected by the therapy. Serum IL-2 levels were only measurable in single patients during the therapy phase. Since verum and placebo groups did not differ with respect to requirement for intravenous gammaglobulin substitutions, n-IL-2 therapy was uneffective in switching on IgG synthesis in vivo. Nevertheless, there was an elevation in vitro of IgM synthesis in 5 patients and of IgG synthesis in 4 patients during n-IL-2 therapy after stimulation of patients' lymphocytes with staphylococcus aureus Cowan I (SAC) plus n-IL-2 or with Pokeweed Mitogen (PWM) without n-IL-2. Additionally, an elevated IL-2-synthesis in vitro was recorded after OKT3 stimulation for 3 CVID patients. There was a significant reduction of severe infections from 25 during the first 6 months of the study to 7 infections during the following 6 months, in the group of patients which received n-IL-2 first. In the second group, which received placebo first, there were no significant differences between placebo and n-IL-2 therapy phase detectable (25 infections during the first 6 months of the study and 24 severe infections in the second phase).(ABSTRACT TRUNCATED AT 250 WORDS)


Betaine Effects on Morphology, Proliferation, and p53-induced Apoptosis of HeLa Cervical Carcinoma Cells in Vitro.
To investigate the effects of betaine on HeLa cell growth and apoptosis and molecular mechanisms. Concentrations of 0.1, 1.0, 5.0, 20.0, 100.0 mg/ml of betaine were used to evaluate the anticancer efficacy for HeLa cells respectively, and MCF-10A was also detected as a normal diploid cell control. We found that proliferation of HeLa cells was inhibited significantly upon exposure to increasing betaine levels with the MTT test (p<0.05). The percentage of S phase cells in the low dose groups (< 5mg/ml) were distinctly higher than in high dose groups, and the rates of Sub-G1 phase were the opposite (p<0.01); A high concentration of betaine (>5.0mg/ml) significantly promoted the apoptosis of HeLa cells (p<0.01). SOD activities of the low dose groups were slightly higher than the control group (p<0.05) and there were obvious synchronicity and correlation among the expression of promoting apoptosis genes Bax, P53, Caspase 3 and apoptosis suppression gene Bcl-2. In response to an apoptosis-inducing stimulus, p53 and cyclin D1 could be activated with blockage of the cell cycle at G1/S or S/G2 checkpoints. Our data showed that betaine could promote HeLa cells proliferation in vitro at low concentrations.In contrast, high concentrations could significantly inhibit cell growth and migration, and induce apoptosis of HeLa cells through caspase 3 signaling and further promoted necrosis. This might imply that betaine exhibits tumoricidal effects and acts as a biological response modifier in cancer treatment by inducing apoptosis and cell cycle arrest in a dose and time-dependent manner.


Quantitative ultrasound measurement of the calcaneus in Southeast Asian children with thalassemia: comparison with dual-energy X-ray absorptiometry.
The purpose of this study was to test the hypothesis that quantitative ultrasound properties of the calcaneus in Southeast Asian children treated for thalassemia have different characteristics than those of their healthy counterparts and thereby can be used for assessing the risk of osteoporosis. Broadband ultrasound attenuation and the speed of sound were measured from groups of thalassemic and healthy children and compared with bone mineral density (BMD) estimated from dual-energy X-ray absorptiometry to determine intergroup and intragroup dependencies of the measurements and variations with differences in sex and anthropometric characteristics. Broadband ultrasound attenuation and speed of sound measurements were found to be independent of sex but dependent on age in the thalassemic children. Consistently, broadband ultrasound attenuation had lower values and the speed of sound had higher values compared with those of the healthy children in each age group. Broadband ultrasound attenuation correlated well with the speed of sound and also with age, weight, and height, but the speed of sound did not show an association with these parameters. Broadband ultrasound attenuation correlated moderately with BMD in the lumbar spine and whole body, but the corresponding association was much weaker for the speed of sound. In the thalassemic children, both broadband ultrasound attenuation and BMD increased with age as they grew older but not fast enough compared with the healthy children, and the risk of osteoporosis was greater at older ages. Calcaneal quantitative ultrasound may be used as a diagnostic screening tool for assessing the bone status in thalassemic Southeast Asian children and for deciding whether further dual-energy X-ray absorptiometry is needed, particularly in those who are at a greater risk for osteoporosis as identified by low body weight and height.


NIR-Light-Triggered Anticancer Strategy for Dual-Modality Imaging-Guided Combination Therapy via a Bioinspired Hybrid PLGA Nanoplatform.
A promising approach toward cancer therapy is expected to integrate imaging and therapeutic agents into a versatile nanocarrier for achieving improved antitumor efficacy and reducing the side effects of conventional chemotherapy. Herein, we designed a poly(d,l-lactic- co-glycolic acid) (PLGA)-based theranostic nanoplatform using the double emulsion solvent evaporation method (W/O/W), which is associated with bovine serum albumin (BSA) modifications, to codeliver indocyanine green (ICG), a widely used near-infrared (NIR) dye, and doxorubicin (Dox), a chemotherapeutic drug, for dual-modality imaging-guided chemo-photothermal combination cancer therapy. The resultant ICG/Dox co-loaded hybrid PLGA nanoparticles (denoted as IDPNs) had a diameter of around 200 nm and exhibited excellent monodispersity, fluorescence/size stability, and biocompatibility. It was confirmed that IDPNs displayed a photothermal effect and that the heat induced faster release of Dox, which led to enhanced drug accumulation in cells and was followed by their efficient escape from the lysosomes into the cytoplasm and drug diffusion into the nucleus, resulting in a chemo-photothermal combinatorial therapeutic effect in vitro. Moreover, the IDPNs exhibited a high ability to accumulate in tumor tissue, owing to the enhanced permeability and retention (EPR) effect, and could realize real-time fluorescence/photoacoustic imaging of solid tumors with a high spatial resolution. In addition, the exposure of tumor regions to NIR irradiation could enhance the tumor penetration ability of IDPNs, almost eradicating subcutaneous tumors. In addition, the inhibition rate of IDPNs used in combination with laser irradiation against EMT-6 tumors in tumor-bearing nude mice (chemo-photothermal therapy) was approximately 95.6%, which was much higher than that for chemo- or photothermal treatment alone. Our study validated the fact that the use of well-defined IDPNs with NIR laser treatment could be a promising strategy for the early diagnosis and passive tumor-targeted chemo-photothermal therapy for cancer.


Purification, characterization and molecular cloning of trichoanguin, a novel type I ribosome-inactivating protein from the seeds of Trichosanthes anguina.
The seeds of the plant Trichosanthes anguina contain a type I ribosome-inactivating protein (RIP), designated trichoanguin, which was purified to apparent homogeneity by the combined use of ion-exchange chromatographies, i.e. first with DE-52 cellulose and then with CM-52 cellulose. The protein was found to be a glycoprotein with a molecular mass of 35 kDa and a pI of 9.1. It strongly inhibits the protein synthesis of rabbit reticulocyte lysate, with an IC50 of 0.08 nM, but only weakly that of HeLa cells, with an IC50 of 6 microM. Trichoanguin cleaves at the A4324 site of rat 28 S rRNA by its N-glycosidase activity. The cDNA of trichoanguin consists of 1039 nt and encodes an open reading frame coding for a polypeptide of 294 amino acid residues. The first 19 residues of this polypeptide encode a signal peptide sequence and the last 30 residues comprise an extension at its C-terminus. There are four potential glycosylation sites, located at Asn-51, Asn-65, Asn-201 and Asn-226. A comparison of the amino acid sequence of trichoanguin with those of RIPs such as trichosanthin, alpha-momorcharin, ricin A-chain and abrin A-chain reveals 55%, 48%, 36% and 34% identity respectively. Molecular homology modelling of trichoanguin indicates that its tertiary structure closely resembles those of trichosanthin and alpha-momorcharin. The large structural similarities might account for their common biological effects such as an abortifacient, an anti-tumour agent and anti-HIV-1 activities. Trichoanguin contains two cysteine residues, Cys-32 and Cys-155, with the former being likely to be located on the protein surface, which is directly amenable for conjugation with antibodies to form immunoconjugates. It is therefore conceivable that trichoanguin might be a better type I RIP than any other so far examined for the preparation of immunotoxins, with a great potential for application as an effective chemotherapeutic agent for the treatment of cancer.


AMEE Guide No. 123 - How to read studies of educational costs.
Healthcare and health professions education share many of the same problems in decision making. In both cases, there is a finite amount of resources, and so choices need to be made between alternatives. To navigate the options available requires effective decision making. Choosing one option requires consideration of its opportunity cost - the benefit forgone of the other competing options. The purpose of this abridged AMEE guide is to introduce educational decision-makers to the economic concept of cost, and how to read studies about educational costs to inform effective cost-conscious decision-making. This guide leads with a brief review of study designs commonly utilized in this field of research, followed by an overview of how study findings are commonly presented. The tutorial will then offer a four-step model for appraising and considering the results of an economic evaluation. It asks the questions: (1) Can I trust the results? (2) What are the results telling me? (3) Could the results be transferred to my context? (4) Should I change my practice?


Orbital-independent superconducting gaps in iron pnictides.
The origin of superconductivity in the iron pnictides has been attributed to antiferromagnetic spin ordering that occurs in close combination with a structural transition, but there are also proposals that link superconductivity to orbital ordering. We used bulk-sensitive laser angle-resolved photoemission spectroscopy on BaFe(2)(As(0.65)P(0.35))(2) and Ba(0.6)K(0.4)Fe(2)As(2) to elucidate the role of orbital degrees of freedom on the electron-pairing mechanism. In strong contrast to previous studies, an orbital-independent superconducting gap magnitude was found for the hole Fermi surfaces. Our result is not expected from the superconductivity associated with spin fluctuations and nesting, but it could be better explained invoking magnetism-induced interorbital pairing, orbital fluctuations, or a combination of orbital and spin fluctuations. Regardless of the interpretation, our results impose severe constraints on theories of iron pnictides.


Prognostic parameters in uveal melanoma and their association with BAP1 expression.
To determine whether BAP1 gene and protein expression associates with different prognostic parameters in uveal melanoma and whether BAP1 expression correctly identifies patients as being at risk for metastases, following enucleation of the primary tumour. Thirty cases of uveal melanoma obtained by enucleation between 1999 and 2004 were analysed for a variety of prognostic markers, including histological characteristics, chromosome aberrations obtained by fluorescence in situ hybridisation (FISH) and single nucleotide polymorphism (SNP) analysis and gene expression profiling. These parameters were compared with BAP1 gene expression and BAP1 immunostaining. The presence of monosomy of chromosome 3 as identified by the different chromosome 3 tests showed significantly increased HRs (FISH on isolated nuclei cut-off 30%: HR 11.6, p=0.002; SNP analysis: HR 20.3, p=0.004) for death due to metastasis. The gene expression profile class 2, based on the 15-gene expression profile, similarly provided a significantly increased HR for a poor outcome (HR 8.5, p=0.005). Lower BAP1 gene expression and negative BAP1 immunostaining (50% of 28 tumours were immunonegative) were both associated with these markers for prognostication: FISH cut-off 30% monosomy 3 (BAP1 gene expression: p=0.037; BAP1 immunostaining: p=0.001), SNP-monosomy 3 (BAP1 gene expression: p=0.008; BAP1 immunostaining: p=0.002) and class 2 profile (BAP1 gene expression: p<0.001; BAP1 immunostaining: p=0.001) and were themselves associated with an increased risk of death due to metastasis (BAP1 gene expression dichotomised: HR 8.7, p=0.006; BAP1 immunostaining: HR 4.0, p=0.010). Loss of BAP1 expression associated well with all of the methods currently used for prognostication and was itself predictive of death due to metastasis in uveal melanoma after enucleation, thereby emphasising the importance of further research on the role of BAP1 in uveal melanoma.


Influence of water quality on zinc toxicity to the Florida apple snail (Pomacea paludosa) and sensitivity of freshwater snails to zinc.
The present study characterized the influence of water-quality characteristics on zinc (Zn) toxicity to the Florida apple snail (Pomacea paludosa) and the sensitivity of freshwater snails to Zn. Standard 96-h renewal acute toxicity tests were conducted with Zn and juvenile P. paludosa under 3 conditions of pH and alkalinity, water hardness, and dissolved organic carbon (DOC). Median lethal effect concentrations (96-h LC50s), no-observed- effect concentrations, lowest-observed-effect concentrations, LC10s, and LC20s were determined for each test. The results showed that Zn toxicity to P. paludosa decreased linearly with increasing hardness, pH, and DOC. A multiple linear regression model based on pH, hardness, and DOC was able to explain 99% of the observed variability in LC50s. These results are useful for the development of a biotic ligand model (BLM) for P. paludosa and Zn. Zinc acute toxicity data were collected from the literature for 12 freshwater snail species in a wide range of water-quality characteristics for species sensitivity distribution analysis. The results showed that P. paludosa is the second most sensitive to Zn. The present study also suggested that aqueous ZnCO3 and ZnHCO3 (-) can be bioavailable to P. paludosa. Therefore, bioavailability models (e.g., BLM) should take these Zn species into consideration for bioavailability when applied to snails.


Quantifying wheat yield across the field as a function of wheat streak mosaic intensity: a state space approach.
Wheat streak mosaic virus (WSMV), vectored by the wheat curl mite Aceria tosichella, is one of the major limiting factors in wheat production in the Texas Panhandle. The mites are blown by wind into wheat fields from nearby volunteer wheat fields or fields supporting vegetation which harbor virulent mites. Consequently, gradients of wheat streak severity are often observed stretching from the edges of wheat fields into the center or beyond. To describe the magnitude of the spatial relationships between grain yield and wheat streak intensity across the field, studies were conducted in 2006 and 2007 in three infected fields. Wheat streak severity was quantified with reflectance measurements (remote sensing) at 555-nm wave length using a hand-held radiometer. Measurements were taken in several equally spaced 1 m(2) locations along a total of eight transects and grain yield was assessed from a 0.8 m(2) area of each location. State space analysis was used to describe the relationships in which yield data and reflectance values were used as dependent and explanatory variables, respectively. A structural time series model was formulated as a state space model where the unobserved components were modeled explicitly. In the analysis the state of yield at current location (d) was related to the state of wheat streak intensity either at current locations (d) or lagged locations with autoregressive values of the first order (d-1) or greater. There were significant cross-correlations between yield and wheat streak intensity up to distances of 150 m (P < or = 0.05). Grain yield at the current position was significantly correlated with reflectance values at the same location and/or at lagged locations. The spatial aspects of the yield-reflectance relationships were best described by state space models with stochastic trends without slopes or deterministic trends with or without slopes. The models correctly predicted almost all of the observed yield values as a function of wheat streak intensity across the field within the 95% confidence interval. Results obtained in this study suggest that state space methodology can be a powerful tool in the study of plant disease spread as a function of other variables.


Ultrastructure and Dynamics of Synaptonemal Complex Components During Meiotic Pairing and Synapsis of Standard (A) and Accessory (B) Rye Chromosomes.
During prophase I a meiosis-specific proteinaceous tripartite structure, the synaptonemal complex (SC), forms a scaffold to connect homologous chromosomes along their lengths. This process, called synapsis, is required in most organisms to promote recombination between homologs facilitating genetic variability and correct chromosome segregations during anaphase I. Recent studies in various organisms ranging from yeast to mammals identified several proteins involved in SC formation. However, the process of SC disassembly remains largely enigmatic. In this study we determined the structural changes during SC formation and disassembly in rye meiocytes containing accessory (B) chromosomes. The use of electron and super-resolution microscopy (3D-SIM) combined with immunohistochemistry and FISH allowed us to monitor the structural changes during prophase I. Visualization of the proteins ASY1, ZYP1, NSE4A, and HEI10 revealed an extensive SC remodeling during prophase I. The ultrastructural investigations of the dynamics of these four proteins showed that the SC disassembly is accompanied by the retraction of the lateral and axial elements from the central region of the SC. In addition, SC fragmentation and the formation of ball-like SC structures occur at late diakinesis. Moreover, we show that the SC composition of rye B chromosomes does not differ from that of the standard (A) chromosome complement. Our ultrastructural investigations indicate that the dynamic behavior of the studied proteins is involved in SC formation and synapsis. In addition, they fulfill also functions during desynapsis and chromosome condensation to realize proper recombination and homolog separation. We propose a model for the homologous chromosome behavior during prophase I based on the observed dynamics of ASY1, ZYP1, NSE4A, and HEI10.


Control efficacy of complex networks.
Controlling complex networks has become a forefront research area in network science and engineering. Recent efforts have led to theoretical frameworks of controllability to fully control a network through steering a minimum set of driver nodes. However, in realistic situations not every node is accessible or can be externally driven, raising the fundamental issue of control efficacy: if driving signals are applied to an arbitrary subset of nodes, how many other nodes can be controlled? We develop a framework to determine the control efficacy for undirected networks of arbitrary topology. Mathematically, based on non-singular transformation, we prove a theorem to determine rigorously the control efficacy of the network and to identify the nodes that can be controlled for any given driver nodes. Physically, we develop the picture of diffusion that views the control process as a signal diffused from input signals to the set of controllable nodes. The combination of mathematical theory and physical reasoning allows us not only to determine the control efficacy for model complex networks and a large number of empirical networks, but also to uncover phenomena in network control, e.g., hub nodes in general possess lower control centrality than an average node in undirected networks.


Development of a simple 12-item theory-based instrument to assess the impact of continuing professional development on clinical behavioral intentions.
Decision-makers in organizations providing continuing professional development (CPD) have identified the need for routine assessment of its impact on practice. We sought to develop a theory-based instrument for evaluating the impact of CPD activities on health professionals' clinical behavioral intentions. Our multipronged study had four phases. 1) We systematically reviewed the literature for instruments that used socio-cognitive theories to assess healthcare professionals' clinically-oriented behavioral intentions and/or behaviors; we extracted items relating to the theoretical constructs of an integrated model of healthcare professionals' behaviors and removed duplicates. 2) A committee of researchers and CPD decision-makers selected a pool of items relevant to CPD. 3) An international group of experts (n = 70) reached consensus on the most relevant items using electronic Delphi surveys. 4) We created a preliminary instrument with the items found most relevant and assessed its factorial validity, internal consistency and reliability (weighted kappa) over a two-week period among 138 physicians attending a CPD activity. Out of 72 potentially relevant instruments, 47 were analyzed. Of the 1218 items extracted from these, 16% were discarded as improperly phrased and 70% discarded as duplicates. Mapping the remaining items onto the constructs of the integrated model of healthcare professionals' behaviors yielded a minimum of 18 and a maximum of 275 items per construct. The partnership committee retained 61 items covering all seven constructs. Two iterations of the Delphi process produced consensus on a provisional 40-item questionnaire. Exploratory factorial analysis following test-retest resulted in a 12-item questionnaire. Cronbach's coefficients for the constructs varied from 0.77 to 0.85. A 12-item theory-based instrument for assessing the impact of CPD activities on health professionals' clinical behavioral intentions showed adequate validity and reliability. Further studies could assess its responsiveness to behavior change following CPD activities and its capacity to predict health professionals' clinical performance.


ADAPT: The Agent Development and Prototyping Testbed.
We present ADAPT, a flexible platform for designing and authoring functional, purposeful human characters in a rich virtual environment. Our framework incorporates character animation, navigation, and behavior with modular interchangeable components to produce narrative scenes. The animation system provides locomotion, reaching, gaze tracking, gesturing, sitting, and reactions to external physical forces, and can easily be extended with more functionality due to a decoupled, modular structure. The navigation component allows characters to maneuver through a complex environment with predictive steering for dynamic obstacle avoidance. Finally, our behavior framework allows a user to fully leverage a character's animation and navigation capabilities when authoring both individual decision-making and complex interactions between actors using a centralized, event-driven model.


Lamotrigine versus carbamazepine monotherapy for epilepsy: an individual participant data review.
This is an updated version of the original Cochrane Review published in Issue 11, 2006 of the Cochrane Database of Systematic Reviews.Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment up to 70% of individuals with active epilepsy have the potential to become seizure-free, and to go into long-term remission shortly after starting drug therapy with a single antiepileptic drug (AED) in monotherapy.The correct choice of first-line AED for individuals with newly diagnosed seizures is of great importance. It is important that the choice of AEDs for an individual is made using the highest quality evidence regarding the potential benefits and harms of the various treatments.Carbamazepine or lamotrigine are recommended as first-line treatments for new onset focal seizures and as a first- or second-line treatment for generalised tonic-clonic seizures. Performing a synthesis of the evidence from existing trials will increase the precision of the results for outcomes relating to efficacy and tolerability and may assist in informing a choice between the two drugs. To review the time to treatment failure, remission and first seizure with lamotrigine compared to carbamazepine when used as monotherapy in people with focal onset seizures (simple or complex focal and secondarily generalised) or generalised onset tonic-clonic seizures (with or without other generalised seizure types). We conducted the first searches for this review in 1997. For the most recent update, we searched the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE, Clinical Trials.gov and the WHO International Clinical Trials Registry Platform on 26 February 2018, without language restrictions SELECTION CRITERIA: Randomised controlled trials comparing monotherapy with either carbamazepine or lamotrigine in children or adults with focal onset seizures or generalised onset tonic-clonic seizures DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Our primary outcome was time to treatment failure and our secondary outcomes were time to first seizure post randomisation, time to six-month, 12-month and 24-month remission, and incidence of adverse events. We used Cox proportional hazards regression models to obtain trial-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), using the generic inverse variance method to obtain the overall pooled HR and 95% CI. We included 14 trials in this review. Individual participant data were available for 2572 participants out of 3787 eligible individuals from nine out of 14 trials: 68% of the potential data. For remission outcomes, a HR of less than one indicated an advantage for carbamazepine; and for first seizure and treatment failure outcomes, a HR of less than one indicated an advantage for lamotrigine.The main overall results were: time to treatment failure for any reason related to treatment (pooled HR adjusted for seizure type: 0.71, 95% CI 0.62 to 0.82, moderate-quality evidence), time to treatment failure due to adverse events (pooled HR adjusted for seizure type: 0.55 (95% CI 0.45 to 0.66, moderate-quality evidence), time to treatment failure due to lack of efficacy (pooled HR for all participants: 1.03 (95% CI 0.75 to 1.41), moderate-quality evidence) showing a significant advantage for lamotrigine compared to carbamazepine in terms of treatment failure for any reason related to treatment and treatment failure due to adverse events, but no different between drugs for treatment failure due to lack of efficacy.Time to first seizure (pooled HR adjusted for seizure type: 1.26, 95% CI 1.12 to 1.41, high-quality evidence) and time to six-month remission (pooled HR adjusted for seizure type: 0.86, 95% CI 0.76 to 0.97, high-quality evidence), showed a significant advantage for carbamazepine compared to lamotrigine for first seizure and six-month remission. We found no difference between the drugs for time to 12-month remission (pooled HR for all participants 0.91, 95% CI 0.77 to 1.07, high-quality evidence) or time to 24-month remission (HR for all participants 1.00, 95% CI 0.80 to 1.25, high-quality evidence), however only two trials followed up participants for more than one year so evidence is limited.The results of this review are applicable mainly to individuals with focal onset seizures; 88% of included individuals experienced seizures of this type at baseline. Up to 50% of the limited number of individuals classified as experiencing generalised onset seizures at baseline may have had their seizure type misclassified, therefore we recommend caution when interpreting the results of this review for individuals with generalised onset seizures.The most commonly reported adverse events for both of the drugs across all of the included trials were dizziness, fatigue, gastrointestinal disturbances, headache and skin problems. The rate of adverse events was similar across the two drugs.The methodological quality of the included trials was generally good, however there is some evidence that the design choice of masked or open-label treatment may have influenced the treatment failure and withdrawal rates of the trials. Hence, we judged the quality of the evidence for the primary outcome of treatment failure to be moderate for individuals with focal onset seizures and low for individuals with generalised onset seizures. For efficacy outcomes (first seizure, remission), we judged the quality of evidence to be high for individuals with focal onset seizures and moderate for individuals with generalised onset seizures. Moderate quality evidence indicates that treatment failure for any reason related to treatment or due to adverse events occurs significantly earlier on carbamazepine than lamotrigine, but the results for time to first seizure suggested that carbamazepine may be superior in terms of seizure control. The choice between these first-line treatments must be made with careful consideration. We recommend that future trials should be designed to the highest quality possible with consideration of masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.


Habituation and desensitization of the Hering-Breuer reflex in rat.
1. Many processes in mammalian and invertebrate central nervous systems exhibit habituation and/or sensitization of their responses to repetitive stimuli. Here, we studied the adaptive behaviours of the respiratory pattern generator in rat on repetitive vagal-afferent stimulation and compared these behaviours obtained in vivo with the reported effects of such stimuli on synaptic transmission in the corresponding signal pathway in vitro. 2. Sustained (1 min) electrical pulsed stimulation of the vagus nerve elicited the classic Hering-Breuer (HB) reflex slowing of the respiratory rhythm followed by a bi-exponential recovery, and a post-stimulus rebound (PR). The recovery from the HB reflex satisfied the classic criteria of habituation. 3. The fast component of the recovery and the PR were abolished by systemic administration of an NMDA receptor antagonist or electrolytic lesioning of the pontine Kolliker-Fuse nucleus. The characteristics of the fast recovery and PR suggest a vagally induced desensitization of the NMDA receptor-dependent pontine input to the respiratory pattern generator. 4. The slow component of recovery persist after both experimental interventions and accounted for the habituation to the vagal input. The characteristics of the slow recovery in vivo were reminiscent of the reported synaptic accommodation in vitro in the medullary region where vagal afferents terminate. 5. The habituation of vagal input and desensitization of pontine input act in concert to offset the HB reflex. Such simultaneous habituation-desensitization in parallel neural pathways with differing sensitivities to NMDA receptor activation represent a hitherto unknown pairing of dual non-associative learning processes in the mammalian brain.


Genome-wide screen for asthma in Puerto Ricans: evidence for association with 5q23 region.
While the number of success stories for mapping genes associated with complex diseases using genome-wide association approaches is growing, there is still much work to be done in developing methods for such studies when the samples are collected from a population, which may not be homogeneous. Here we report the first genome-wide association study to identify genes associated with asthma in an admixed population. We genotyped 96 Puerto Rican moderate to severe asthma cases and 88 controls as well as 109 samples representing Puerto Rico's founding populations using the Affymetrix GeneChip Human Mapping 100K array sets. The data from samples representing Puerto Rico's founding populations was used to identify ancestry informative markers for admixture mapping analyses. In addition, a genome-wide association analysis using logistic regression was performed on the data. Although neither admixture mapping nor regression analysis gave any significant association with asthma after correction for multiple testing, an overlap analysis using the top scoring SNPs from different methods suggested chromosomal regions 5q23.3 and 13q13.3 as potential regions harboring genes for asthma in Puerto Ricans. The validation analysis of these two regions in 284 Puerto Rican asthma trios gave significant association for the 5q23.3 region. Our results provide strong evidence that the previously linked 5q23 region is associated with asthma in Puerto Ricans. The detection of causative variants in this region will require fine mapping and functional validation.


Epigenetic reprogramming during spermatogenesis and male factor infertility.
Infertility is an often devastating diagnosis encountered by around one in six couples who are trying to conceive. Moving away from the long-held belief that infertility is primarily a female issue, it is now recognised that half, if not more, of these cases may be due to male factors. Recent evidence has suggested that epigenetic abnormalities in chromatin dynamics, DNA methylation or sperm-borne RNAs may contribute to male infertility. In light of advances in deep sequencing technologies, researchers have been able to increase the coverage and depth of sequencing results, which in turn has allowed more comprehensive analyses of spermatozoa chromatin dynamics and methylomes and enabled the discovery of new subsets of sperm RNAs. This review examines the most current literature related to epigenetic processes in the male germline and the associations of aberrant modifications with fertility and development.


Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non-Small Cell Lung Cancers.
Oncogene-specific changes in cellular signaling have been widely observed in lung cancer. Here, we investigated how these alterations could affect signaling heterogeneity and suggest novel therapeutic strategies. We compared signaling changes across six human bronchial epithelial cell (HBEC) strains that were systematically transformed with various combinations of TP53, KRAS, and MYC-oncogenic alterations commonly found in non-small cell lung cancer (NSCLC). We interrogated at single-cell resolution how these alterations could affect classic readouts (β-CATENIN, SMAD2/3, phospho-STAT3, P65, FOXO1, and phospho-ERK1/2) of key pathways commonly affected in NSCLC. All three oncogenic alterations were required concurrently to observe significant signaling changes, and significant heterogeneity arose in this condition. Unexpectedly, we found two mutually exclusive altered subpopulations: one with STAT3 upregulation and another with SMAD2/3 downregulation. Treatment with a STAT3 inhibitor eliminated the upregulated STAT3 subpopulation, but left a large surviving subpopulation with downregulated SMAD2/3. A bioinformatics search identified BCL6, a gene downstream of SMAD2/3, as a novel pharmacologically accessible target of our transformed HBECs. Combination treatment with STAT3 and BCL6 inhibitors across a panel of NSCLC cell lines and in xenografted tumors significantly reduced tumor cell growth. We conclude that BCL6 is a new therapeutic target in NSCLC and combination therapy that targets multiple vulnerabilities (STAT3 and BCL6) downstream of common oncogenes, and tumor suppressors may provide a potent way to defeat intratumor heterogeneity. Cancer Res; 77(11); 3070-81. ©2017 AACR.


Complete genome sequence of a velogenic neurotropic avian paramyxovirus 1 isolated from peacocks (Pavo cristatus) in a wildlife park in Pakistan.
Avian paramyxovirus serotype 1 (APMV-1) was isolated from an acute and highly contagious outbreak in peacocks (Pavo cristatus) in a wildlife park in Pakistan. A velogenic neurotropic form of APMV-1 caused a 100% case fatality rate and killed 190 peacocks within a week. Biological and serological characterizations showed features of a velogenic strain of APMV-1, and these results were further confirmed by sequence analysis of the cleavage site in the fusion protein. The complete genome of one of the isolates was sequenced, and phylogenetic analysis was conducted. The analysis showed that this isolate belonged to genotype VII, specifically, to subgenotype VIIa, and clustered closely with isolates characterized from Indonesia in the 1990s. Interestingly, the isolate showed significant differences from previously characterized APMV-1 isolates from commercial and rural chickens in Pakistan. The work presented here is the first complete genome sequence of any APMV-1 isolate from wild birds in the region and therefore highlights the need for increased awareness and surveillance in such bird species.


Nucleolar assembly of the rRNA processing machinery in living cells.
To understand how nuclear machineries are targeted to accurate locations during nuclear assembly, we investigated the pathway of the ribosomal RNA (rRNA) processing machinery towards ribosomal genes (nucleolar organizer regions [NORs]) at exit of mitosis. To follow in living cells two permanently transfected green fluorescence protein-tagged nucleolar proteins, fibrillarin and Nop52, from metaphase to G1, 4-D time-lapse microscopy was used. In early telophase, fibrillarin is concentrated simultaneously in prenucleolar bodies (PNBs) and NORs, whereas PNB-containing Nop52 forms later. These distinct PNBs assemble at the chromosome surface. Analysis of PNB movement does not reveal the migration of PNBs towards the nucleolus, but rather a directional flow between PNBs and between PNBs and the nucleolus, ensuring progressive delivery of proteins into nucleoli. This delivery appeared organized in morphologically distinct structures visible by electron microscopy, suggesting transfer of large complexes. We propose that the temporal order of PNB assembly and disassembly controls nucleolar delivery of these proteins, and that accumulation of processing complexes in the nucleolus is driven by pre-rRNA concentration. Initial nucleolar formation around competent NORs appears to be followed by regroupment of the NORs into a single nucleolus 1 h later to complete the nucleolar assembly. This demonstrates the formation of one functional domain by cooperative interactions between different chromosome territories.


Outcome after rapid vs gradual discontinuation of lithium treatment in bipolar disorders.
Withdrawal of bipolar mood disorder (BP-I) patients from prolonged, stable lithium maintenance has a high risk of early recurrence, particularly of mania. We thus compared risks of stopping lithium rapidly vs gradually. Outpatients undergoing clinically determined discontinuation of lithium treatment at different rates were followed up prospectively to 5 years. Risks and timing of new episodes were analyzed. Subjects (N = 64) with a DSM-III-R BP disorder, previously stable on lithium monotherapy for 18 to 120 months (mean, 3.6 years) were followed up clinically after discontinuing lithium (elected in prolonged wellbeing in 67%). None was unavailable for follow-up, and subtyping (BP-I or BP-II) remained stable. Within 5 years, 75% had a recurrent episode; BP-I patients were 1.5-times less likely than BP-II to remain in remission. Polarity of first-recurrent and onset episodes was 80.8% concordant. Overall risk of a new episode of mania was significantly greater after rapid (< 2) than gradual (2 to 4 weeks discontinuation (5-year hazard ratio = 2.8); the difference in risk of depression was even greater hazard ratio = 5.4). Recurrence rate was more elevated within months of rapid discontinuation (12-month hazard ratio = 5.4). Recurrence rate was more elevated within months of rapid discontinuation (12-month hazard ratio = 4.3) than at later times (2 to 5 years), when courses of "survival" over time were nearly parallel in both discontinuation groups. Risk of early recurrence of BP disorder following discontinuation of lithium maintenance is elevated, but may be both predictable (timing and polarity) and modifiable by gradual discontinuation.


On generalized fixed sequence procedures for controlling the FWER.
Testing a sequence of pre-ordered hypotheses to decide which of these can be rejected or accepted while controlling the familywise error rate (FWER) is of importance in many scientific studies such as clinical trials. In this paper, we first introduce a generalized fixed sequence procedure whose critical values are defined by using a function of the numbers of rejections and acceptances, and which allows follow-up hypotheses to be tested even if some earlier hypotheses are not rejected. We then construct the least favorable configuration for this generalized fixed sequence procedure and present a sufficient condition for the FWER control under arbitrary dependence. Based on the condition, we develop three new generalized fixed sequence procedures controlling the FWER under arbitrary dependence. We also prove that each generalized fixed sequence procedure can be described as a specific closed testing procedure. Through simulation studies and a clinical trial example, we compare the power performance of these proposed procedures with those of the existing FWER controlling procedures. Finally, when the pairwise joint distributions of the true null p-values are known, we further improve these procedures by incorporating pairwise correlation information while maintaining the control of the FWER. Copyright © 2015 John Wiley & Sons, Ltd.


Incomplete intestinal metaplasia as an indicator for early detection of gastric carcinoma in the events of helicobacter pylori positive chronic atrophic gastritis.
The aim of the study was to ascertain the existence of intestinal metaplasia in gastric mucosa of patients with gastric carcinoma coupled with H. pylori positive chronic atrophic gastritis and possible connection of IM with the development of gastric carcinoma. The paper presents prospective study that included 50 patients with gastric carcinoma and 50 patients with chronic atrophic H. pylori positive gastritis. All the patients were subjected to gastroscopy as well as biopsy targeted at antrum, lesser curvature and corpus and at the area 1-2 cm removed from tumor lesion. Biopsy samples were sliced by microtome and stained. We analyzed presence, frequency and severity of inflammatory-regenerative, metaplastic and dysplastic changes in the mucosa and evaluated their prognostic value. We typed IM immunohistochemically. This study confirmed responsibility of H. pylori for inflammatory events in gastric mucosa in patients with gastric carcinoma. According to our findings incomplete IM of types IIa and IIb as precancerous lesion is responsible for the development of gastric carcinoma and is associated with chronic atrophic gastritis grade I and II (92% of subjects, p=0.0097, h=1, p=0.01). Thus, the finding of incomplete intestinal metaplasia may be used as an indicator for early gastric carcinoma detection. Patients with patho-histologically verified incomplete intestinal metaplasia associated with active chronic atrophic gastritis of levels I and II represent risk group for the development of gastric carcinoma of intestinal type.


Promoting Weight Maintenance among Overweight and Obese Hispanic Children in a Rural Practice.
US Hispanic children experience a disproportionate burden of overweight and obesity. Comprehensive high-intensity behavioral programs have demonstrated effectiveness in improving weight status among obese children. However, there remains a need to develop more efficient interventions that are feasible in primary care and demonstrate effectiveness in Hispanic children. The pilot study used a two-group randomized design. Eligible overweight (BMI between the 85th and 94th percentile for age and gender) or obese (BMI ≥95th percentile) Hispanic children and their parents (N=118 child/parent dyads) were recruited from a rural pediatric clinic and randomized to: standard care (SC; n=61 dyads) or behavioral intervention (INT; n=57 dyads). The primary outcomes-weight, waist circumference, and zBMI-were measured at baseline, 2, 6, and 18 weeks. Multivariate logistic regression was used to examine the effect of INT on the likelihood of weight maintenance adjusting for potential confounding variables. Significantly fewer INT children (68.5%) experienced weight gain, compared to SC children (89.7%; p=0.009). The same pattern was observed for waist circumference, where fewer INT children (44%) experienced an increase in waist circumference, compared to SC children (68.6%; p=0.02). Although a trend of improvement in favor of the INT was observed for zBMI, it was not significant. This study provides preliminary evidence for the feasibility of a primary-care-based approach to promoting weight maintenance among a high-risk population.


Transforming growth factor beta 1 selectively regulates early murine hematopoietic progenitors and inhibits the growth of IL-3-dependent myeloid leukemia cell lines.
Transforming growth factor beta 1 (TGF-beta 1) has been shown to be associated with active centers of hematopoiesis and lymphopoiesis in the developing fetus. Therefore, the effects of TGF-beta 1 on mouse hematopoiesis were studied. TGF-beta 1 is a potent inhibitor of IL-3-induced bone marrow proliferation, but it does not inhibit the proliferation induced by granulocyte/macrophage, colony-stimulating factor (CSF), granulocyte CSF, and erythropoietin (Epo). TGF-beta 1 also inhibits IL-3-induced multipotential colony formation of bone marrow cells in soft agar, which includes early erythroid differentiation, while Epo-induced terminal differentiation is unaffected. In addition, IL-3-induced granulocyte/macrophage colonies were inhibited; however, small clusters of differentiated myeloid cells were consistently seen in cultures containing IL-3 and TGF-beta 1. Thus, TGF-beta 1 selectively inhibits early hematopoietic progenitor growth and differentiation but not more mature progenitors. TGF-beta 1 is also a potent inhibitor of IL-3-dependent and -independent myelomonocytic leukemic cell growth, while the more mature erythroid and macrophage leukemias are insensitive. Therefore, TGF-beta 1 functions as a selective regulator of differentiating normal hematopoietic cells, and suppresses myeloid leukemic cell growth.


Hyperacute graft dysfunction in an orthotopic heart transplant in the presence of non-HLA antibodies.
Antibody-mediated rejection (AMR) in heart transplants in the absence of anti-HLA donor-specific antibody (DSA) is not well studied or documented. This case reviews hyperacute fulminant graft dysfunction suspected to be mediated by non-HLA antibodies. After cross clamp removal, the patient developed severe pulmonary edema, profound coagulopathy, and biventricular failure. The patient's presumed AMR, cardiogenic shock, and coagulopathy were treated with extracorporeal membrane oxygenation (ECMO), plasmapheresis, intravenous immunoglobulin (IVIG), multiple blood products, and prothrombin complex concentrate. The recipient was 0% panel-reactive antibody (PRA), ABO, and crossmatch compatible. Intraoperative biopsy sample revealed a thrombotic process suggestive of a coagulation pathway activated by AMR; however, no C4d deposition was detected. Postmortem biopsies also suggested AMR. Retrospective testing of the patient's pretransplant serum revealed strong antiangiotensin II type 1 receptor (AT1R) antibodies and a strongly positive endothelial cell crossmatch. Anti-AT1R antibodies are known to be AT1 receptor agonists and may trigger inflammation and activate the extrinsic coagulation pathway. Given the potential effects of signaling through the AT1R, the patient's preexisting anti-AT1R antibodies and procoagulant therapy may have adversely affected the patient's clinical course.


Influence and predictive capacity of climate anomalies on daily to decadal extremes in canopy photosynthesis.
Significant advances have been made over the past decades in capabilities to simulate diurnal and seasonal variation of leaf-level and canopy-scale photosynthesis in temperate and boreal forests. However, long-term prediction of future forest productivity in a changing climate may be more dependent on how climate and biological anomalies influence extremes in interannual to decadal variability of canopy ecosystem carbon exchanges. These exchanges can differ markedly from leaf level responses, especially owing to the prevalence of long lags in nutrient and water cycling. Until recently, multiple long-term (10+ year) high temporal frequency (daily) observations of canopy exchange were not available to reliably assess this claim. An analysis of one of the longest running North American eddy covariance flux towers reveals that single climate variables do not adequately explain carbon exchange anomalies beyond the seasonal timescale. Daily to weekly lagged anomalies of photosynthesis positively autocorrelate with daily photosynthesis. This effect suggests a negative feedback in photosynthetic response to climate extremes, such as anomalies in evapotranspiration and maximum temperature. Moisture stress in the prior season did inhibit photosynthesis, but mechanisms are difficult to assess. A complex interplay of integrated and lagged productivity and moisture-limiting factors indicate a critical role of seasonal thresholds that limit growing season length and peak productivity. These results lead toward a new conceptual framework for improving earth system models with long-term flux tower observations.


A null mutation in inositol polyphosphate 4-phosphatase type I causes selective neuronal loss in weeble mutant mice.
Weeble mutant mice have severe locomotor instability and significant neuronal loss in the cerebellum and in the hippocampal CA1 field. Genetic mapping was used to localize the mutation to the gene encoding inositol polyphosphate 4-phosphatase type I (Inpp4a), where a single nucleotide deletion results in a likely null allele. The substrates of INPP4A are intermediates in a pathway affecting intracellular Ca(2+) release but are also involved in cell cycle regulation through binding the Akt protooncogene; dysfunction in either may account for the neuronal loss of weeble mice. Although other mutations in phosphoinositide enzymes are associated with synaptic defects without neuronal loss, weeble shows that Inpp4a is critical for the survival of a subset of neurons during postnatal development in mice.


Vertigo and vestibular abnormalities in spinocerebellar ataxia type 6.
Spinocerebellar ataxia type 6 (SCA6) is a calcium channelopathy due to a pathological CAG repeat expansion in CACNL1A4. Patients frequently describe paroxysmal vertigo early in the disease course, but it is not clear whether this is central or labyrinthine in origin. To address this issue we studied 21 SCA6 patients. Symptoms of vertigo were defined using a structured questionnaire. Signs were recorded during a standardised bed-side vestibular examination that included systematic positional testing with Frenzel goggles.Brief, recurrent attacks of vertigo occurred in 13 patients, usually preceding the onset of ataxia. Nystagmus was observed behind Frenzel goggles in 14 patients, and was induced either during positional testing, or head shaking in 20 patients. Only one patient had findings typical of benign paroxysmal positional vertigo (BPPV). Combined downbeat and horizontal gaze-evoked nystagmus ("side-pocket") was the most common form, occurring most commonly in supine and head-hanging positions, and following horizontal head-shaking. Nystagmus beating away from the ground (apogeotropic) occurred in 9 patients as they lay on their side.In conclusion, vertigo and abnormalities on bedside vestibular examination are common in SCA6, with forms of nystagmus typical of cerebellar, rather than labyrinthine, disease. These findings demonstrate phenotypic overlap between SCA6 and episodic ataxia type 2, which are both due to mutations in CACNL1A4.


Nurse-led titration of angiotensin converting enzyme inhibitors, beta-adrenergic blocking agents, and angiotensin receptor blockers for people with heart failure with reduced ejection fraction.
Heart failure is associated with high mortality and hospital readmissions. Beta-adrenergic blocking agents, angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) can improve survival and reduce hospital readmissions and are recommended as first-line therapy in the treatment of heart failure. Evidence has also shown that there is a dose-dependent relationship of these medications with patient outcomes. Despite this evidence, primary care physicians are reluctant to up-titrate these medications. New strategies aimed at facilitating this up-titration are warranted. Nurse-led titration (NLT) is one such strategy. To assess the effects of NLT of beta-adrenergic blocking agents, ACEIs, and ARBs in patients with heart failure with reduced ejection fraction (HFrEF) in terms of safety and patient outcomes. We searched the Cochrane Central Register of Controlled Trials in the Cochrane Library (CENTRAL Issue 11 of 12, 19/12/2014), MEDLINE OVID (1946 to November week 3 2014), and EMBASE Classic and EMBASE OVID (1947 to 2014 week 50). We also searched reference lists of relevant primary studies, systematic reviews, clinical trial registries, and unpublished theses sources. We used no language restrictions. Randomised controlled trials (RCTs) comparing NLT of beta-adrenergic blocking agents, ACEIs, and/or ARBs comparing the optimisation of these medications by a nurse to optimisation by another health professional in patients with HFrEF. Two review authors (AD & JC) independently assessed studies for eligibility and risk of bias. We contacted primary authors if we required additional information. We examined quality of evidence using the GRADE rating tool for RCTs. We analysed extracted data by risk ratio (RR) with 95% confidence interval (CI) for dichotomous data to measure effect sizes of intervention group compared with usual-care group. Meta-analyses used the fixed-effect Mantel-Haenszel method. We assessed heterogeneity between studies by Chi(2) and I(2). We included seven studies (1684 participants) in the review. One study enrolled participants from a residential care facility, and the other six studies from primary care and outpatient clinics. All-cause hospital admission data was available in four studies (556 participants). Participants in the NLT group experienced a lower rate of all-cause hospital admissions (RR 0.80, 95% CI 0.72 to 0.88, high-quality evidence) and fewer hospital admissions related to heart failure (RR 0.51, 95% CI 0.36 to 0.72, moderate-quality evidence) compared to the usual-care group. Six studies (902 participants) examined all-cause mortality. All-cause mortality was also lower in the NLT group (RR 0.66, 95% CI 0.48 to 0.92, moderate-quality evidence) compared to usual care. Approximately 27 deaths could be avoided for every 1000 people receiving NLT of beta-adrenergic blocking agents, ACEIs, and ARBs. Only three studies (370 participants) reported outcomes on all-cause and heart failure-related event-free survival. Participants in the NLT group were more likely to remain event free compared to participants in the usual-care group (RR 0.60, 95% CI 0.46 to 0.77, moderate-quality evidence). Five studies (966 participants) reported on the number of participants reaching target dose of beta-adrenergic blocking agents. This was also higher in the NLT group compared to usual care (RR 1.99, 95% CI 1.61 to 2.47, low-quality evidence). However, there was a substantial degree of heterogeneity in this pooled analysis. We rated the risk of bias in these studies as high mainly due to a lack of clarity regarding incomplete outcome data, lack of reporting on adverse events associated with the intervention, and the inability to blind participants and personnel. Participants in the NLT group reached maximal dose of beta-adrenergic blocking agents in half the time compared with participants in usual care. Two studies reported on adverse events; one of these studies stated there were no adverse events, and the other study found one adverse event but did not specify the type or severity of the adverse event. Participants in the NLT group experienced fewer hospital admissions for any cause and an increase in survival and number of participants reaching target dose within a shorter time period. However, the quality of evidence regarding the proportion of participants reaching target dose was low and should be interpreted with caution. We found high-quality evidence supporting NLT as one strategy that may improve the optimisation of beta-adrenergic blocking agents resulting in a reduction in hospital admissions. Despite evidence of a dose-dependent relationship of beta-adrenergic blocking agents, ACEIs, and ARBs with improving outcomes in patients with HFrEF, the translation of this evidence into clinical practice is poor. NLT is one strategy that facilitates the implementation of this evidence into practice.


Segment-specific differences in the inward rectifier K(+) current along the renal interlobular artery.
We investigated the role of the inward rectifier K(+) channel (K(IR)) in the renal interlobular artery (ILA). The ILA supplies the afferent arteriole and ranges in diameter from >100 µm near its origin at the arcuate artery to <30 µm at its most distal segment. Vasodilatory responses to elevated extracellular K(+) (15 mmol/L) and vasoconstrictor responses due to K(IR) blockade by Ba(2+) (10-100 µmol/L) were assessed in in vitro perfused hydronephrotic rat kidneys. The distal ILA (26 ± 1 µm) exhibited K(+)-induced dilation and Ba(2+)-induced vasoconstriction, whereas neither response was observed in the proximal ILA (108 ± 3 µm). The intermediate ILA (55 ± 1 µm) exhibited a modest K(+)-induced vasodilatation, but no Ba(2+)-induced vasoconstriction. The K(+)-induced dilations were blocked by Ba(2+), but not by ouabain. Ba(2+)-induced depolarization, measured in ILA segments from normal kidneys, decreased with the increasing diameter. Patch-clamp studies demonstrated that the K(IR) current (I(KIR)) density also was inversely correlated with ILA segment diameter. Myocytes from afferent arterioles and distal ILAs exhibited similarly large I(KIR), whereas this current was absent in proximal ILA myocytes. Finally, we found that Ba(2+) attenuated myogenic vasoconstriction, suggesting an involvement of I(KIR). The previously shown pattern of myogenic reactivity of the ILA (distal > intermediate > proximal) mirrors the distribution of I(KIR) reported in the present study, further supporting a role for I(KIR). Our findings indicate differences in the magnitude of I(KIR) along the ILA and suggest that the influence of K(IR) on reactivity increases as vessel diameter decreases from proximal to distal regions.


Critical reflections on the currently leading definition of sustainable employability.
Sustainable employability (SE) is an important topic as it deals with employees' abilities to function adequately at work and in the labor market throughout their working lives. However, until now there has been only one attempt to define SE in the international literature (1). This first definition is a valuable contribution to the field as it rightfully describes SE as a multidimensional concept, recognizes the importance of both employee and work characteristics, and acknowledges the inherently longitudinal nature of SE. Despite these merits, we argue that this definition of SE has some serious omissions that are important in capturing SE comprehensively. Specifically, we argue that the definition could be improved in various ways, namely, it should: (i) clarify which aspects of employment constitute someone's SE; (ii) not counterintuitively treat SE as a characteristic of both the job and the employee simultaneously; (iii) not be based on the insufficiently tested assumption that achieving value in work inherently leads to SE; (iv) be formulated in a way that SE can also apply to unemployed individuals; and (v) adequately specify how the inherently longitudinal dimension of SE should be addressed. We would like to contribute to the discussion by providing guidelines for a new adjusted definition of SE that could facilitate further research on this important concept and its determinants. Introduction SE is a topic of vital importance to individual employees, organizations and society alike. It generally refers to employees' capacities to function in work throughout their working life. As participation in work is important for individuals, organizations, and society as a whole, individuals' ability to function in work is essential. For individuals, work provides meaning, financial security as well as social contacts. Organizations need productive employees to survive. Also from a societal perspective, it is important that as many people as possible participate in the labor market to maintain economic welfare (1). Moreover, as a consequence of population aging (2-6), longevity, rapid changes in technology (7, 8) and changes in the nature of work (1), both the need to promote sustainable employability of individuals in society and the complexity to succeed in doing so increase even further. Only recently, van der Klink et al provided the first definition of the concept in the international scientific literature (1, p74): "Sustainable employability means that throughout their working lives, workers can achieve tangible opportunities in the form of a set of capabilities. They also enjoy the necessary conditions that allow them to make a valuable contribution through their work, now and in the future, while safeguarding their health and welfare. This requires, on the one hand, a work context that facilitates this for them and, on the other, the attitude and motivation to exploit these opportunities." This definition is accompanied by an equally recent operationalization of SE as a set of capabilities (9). Moreover, the definition itself also appeared in an earlier Dutch publication (10), which other international publications about SE most commonly refer to [ie, in comparison with other definitions in the non-international (eg, Dutch) literature] (11-13). As mentioned, the present paper provides a critical reflection on van der Klink et al's aforementioned definition of SE (1). Merits Van der Klink et al's definition of SE (1) has three important merits. First, SE is seen as a multidimensional construct. It is presented as consisting of a broad set of opportunities for employees to create value for themselves and for their employer that cover various aspects of working. Moreover, the individual's health and well-being as well as attitudinal and motivational aspects are included in the definition as well. This acknowledgement of the multidimensionality of SE is favorable, as it illustrates the complexity of the construct and of what constitutes functioning in work. This is in accordance with the International Classification of Functioning, Disability and Health (ICF) (14), in which functioning is seen from three different perspectives (body, activities, and participation). The ICF underlines the multifaceted and complex nature of functioning in which disease, environmental factors, and personal factors play a role. Similarly, the multifaceted nature of functioning is also illustrated by the fact that different disciplines focus on different aspects to understand functioning at work (15, 16). Second, SE is (partially) defined as the degree to which (i) employees are able to work throughout their entire working lives, and (ii) their work context enables them to do so. This suggests that SE is a set of interacting characteristics of the employee and the work context that codetermine the opportunities and conditions affecting employees' capacity to participate in the labor market throughout their working lives. As such, the definition describes an equal responsibility for employee and employer to maintain the employee's ability to work. This could be considered as a great merit, as research shows how strongly an employee's ability to function is influenced by both the individual, work and work-contextual factors (17). Third, van der Klink et al's definition recognizes that SE is an inherently longitudinal construct as clearly embedded in the words "throughout their working lives". This is essential as "sustainable" necessarily implies a time dimension. Need for further development Despite the aforementioned merits, there are important needs for improvement of van der Klink et al's definition of SE. First, it is not immediately clear from the definition what particular element(s) of the work situation constitute(s) SE. The paper provides some clarity by equating SE with the capability set it propagates, as evidenced by these statements: "… in an accompanying paper also published in this issue, we report on the development and validation of a questionnaire that allows for the assessment of sustainable employability based on the concept of capability" (1, p72) and "This [capability] set, in our view, represents the best possible operationalization of sustainable employability" (1, p74). However, in the paper, SE is also referred to as being determined by a worker's capability: "this model holds that an individual's sustainable employability is determined by how he or she succeeds in converting resources into capabilities, and subsequently into work functioning, in such a way that values such as security, recognition and meaning are met"(1, p72). As it is not feasible that SE is predicted by itself in the form of a capability set, perhaps the capability set does not actually refer to SE itself but rather to a favorable employment situation that may cause SE. More clarity on this issue is needed. Second, the definition seems to treat SE as a characteristic of both the job and the individual at the same time. This is counterintuitive and problematic as the job and work context may predict an individual's ability to be sustainably employed, but they can never be aspects that are part of SE. Instead, employability is a characteristic of the individual alone. Of course the individual's ability to be employed does depend on work and work-contextual factors, but these should be predictors and not be embedded in the construct itself. For an adequate definition of SE, it is essential to disentangle these relationships between causes (employment) and effects (employability). Moreover, future approaches should treat SE as an individual characteristic that is an outcome of the complex interaction between other individual, work, and work-contextual characteristics. Third, the definition and operationalization of SE assume that achieving value in work inherently predicts SE and that, therefore, SE can be conceptualized as achieving value in work. This is problematic, as before such claims can be made, such relationships need to be tested with SE as criterion. This is, however, impossible within the approach van der Klink et al provides. (1), as SE is equated with its predictor(s). Therefore, similar to the first conceptual issue, it seems unlikely that the capability set adequately reflects SE. Fourth, the definition by van der Klink et al (1) suggests that SE only applies to individuals who are employed. In the Abma et al publication (9), which accompanies van der Klink's definition paper as a validation paper, this is shown by the way in which capabilities are measured. Moreover, the definition also suggests this because individuals can only be considered to be sustainably employable if their work context enables them to achieve tangible opportunities. However, individuals who are not currently working can still be highly employable and even sustainably so, but just be between jobs. It is therefore not required for individuals to be enabled by their employer to be sustainably employable. Consequently, in line with our aforementioned points on improving the definition, being enabled by an employer to achieve value may be an important predictor of SE, but it is not necessarily part of SE itself. Moreover, future approaches to SE should define the concept in such a way that it is applicable to every individual regardless of employment status. Finally, the definition and operationalization of SE in the form of a capability set do not include any specification on how the longitudinal aspect of SE should be captured. The definition rightfully acknowledges the longitudinal dimension of SE, but its operationalization focuses solely on achieving value. Although achieving value at work may be an important predictor of SE, a complete operationalization and definition should include its longitudinal nature as well. Outlook In conclusion, while van der Klink et al's definition of SE (1) does have strong merits, it requires further improvement. The approach's main drawback is that capabilities seem more apt at describing a potentially important set of predictor(s) of SE than at capturing the construct itself. Either way, future developments in conceptualizing SE should build on the aforementioned merits, but also define SE in a way that (i) clearly labels which aspects of the employment situation constitute SE; (ii) explicitly separates causes and effects; (iii) treats SE as an individual characteristic that may be affected by other employment characteristics at the individual, work, and work-contextual levels; (iv) makes the concept applicable to any individual regardless of their employment status; and (v) clearly addresses the longitudinal nature of SE as embedded in the word "sustainable". These guidelines should not only enable the development of an appropriate definition of SE but also a conceptually sound way of measuring the construct.


Concurrent measurement of microbiome and allergens in the air of bedrooms of allergy disease patients in the Chicago area.
The particulate and biological components of indoor air have a substantial impact on human health, especially immune respiratory conditions such as asthma. To better explore the relationship between allergens, the microbial community, and the indoor living environment, we sampled the bedrooms of 65 homes in the Chicago area using 23the patient-friendly Inspirotec electrokinetic air sampling device, which collects airborne particles for characterization of both allergens and microbial DNA. The sampling device captured sufficient microbial material to enable 16S rRNA amplicon sequencing data to be generated for every sample in the study. Neither the presence of HEPA filters nor the height at which the air sampling device was placed had any influence on the microbial community profile. A core microbiota of 31 OTUs was present in more than three quarters of the samples, comprising around 45% of the relative sequence counts in each bedroom. The most abundant single organisms were Staphylococcus, with other core taxa both human and outdoor-associated. Bacterial alpha diversity was significantly increased in bedrooms that reported having open windows, those with flowering plants in the vicinity, and those in homes occupied by dogs. Porphyromonas, Moraxella, Sutterella, and Clostridium, along with family Neisseraceae, were significantly enriched in homes with dogs; interestingly, cats did not show a significant impact on microbial diversity or relative abundance. While dog allergen load was significantly correlated with bacterial alpha diversity, the taxa that significantly correlated with allergen burden did not exclusively overlap with those enriched in homes with dogs. Alternaria allergen load was positively correlated with bacterial alpha diversity, while Aspergillus allergen load was negatively correlated. The Alternaria allergen load was also significantly correlated with open windows. Microbial communities were significantly differentiated between rural, suburban, and urban homes and houses that were physically closer to each other maintained significantly more similar microbiota. We have demonstrated that it is possible to determine significant associations between allergen burden and the microbiota in air from the same sample and that these associations relate to the characteristics of the home and neighborhoods.


Predictors of procedural complications in adult Fontan patients undergoing non-cardiac procedures.
Limited data exist regarding the outcomes of non-cardiac procedures (NCPs) in adult patients after Fontan operations (Fontan patients). To compare procedural outcomes after NCPs in Fontan patients with outcomes for two matched control groups: patients with repaired congenital heart disease and biventricular circulation (CHD-BiV) and patients with no heart disease (NHD). We defined cyanosis as oxygen saturation <90% and procedural hypoxia as saturation <80% or a decrease in saturation >10% from baseline. There were 538 NCPs in 154 Fontan patients (mean age, 30 years) performed in 1990-2015. Sedation and anaesthesia types were monitored anaesthesia care (256,48%), general anaesthesia (51,9%), minimal sedation (105,20%), local anaesthesia (75,14%) and regional anaesthesia (51,9%). Ninety-three complications occurred in 79 procedures (15%) and included arrhythmia requiring intervention (9), hypotension (14), bradycardia (8), hypoxia (38), heart failure requiring intravenous diuretics (2), acute kidney injury (3), bleeding requiring blood transfusion (1), unplanned procedures for dialysis catheter placement (2), readmission (2), unplanned hospitalisation for hypoxia (8) and unplanned transfer to intensive care unit (1). Baseline cyanosis was the only multivariable risk factor for complications (HR, 1.87 (95% CI 1.14 to 3.67), p=0.04). Procedural complications were more common in the Fontan group (18%) than in the CHD-BiV (5%) and NHD groups (1.4%) (p=0.001). Complications after NCPs were more common in Fontan patients, and baseline cyanosis was a risk factor for complications. All-cause mortality was low and may be related to the multidisciplinary care approach used for Fontan patients at our centre.


Total sesquiterpene lactones prepared from Inula helenium L. has potentials in prevention and therapy of rheumatoid arthritis.
Inula helenium L. is an herb with anti-inflammatory properties. Sesquiterpene lactones (SLs), mainly alantolactone (AL) and isoalantolactone (IAL), are considered as its active ingredients. However, the anti-inflammatory effects of SL-containing extracts of I. helenium have not been explored. Here we prepared total SLs from I. helenium (TSL-IHL), analyzed its chemical constituents, and performed cellular and animal studies to evaluate its anti-inflammatory activities. The chemical profile of TSL-IHL was analyzed by HPLC-UV. Its in vitro effects on the activation of signaling pathways and expression of inflammatory genes were examined by western blotting and quantitative real-time PCR, respectively, and compared with those of AL and IAL. Its in vivo anti-inflammatory effects were evaluated in adjuvant- and collagen-induced arthritis rat models. Chemical analysis showed that AL and IAL represent major constituents of TSL-IHL. TSL-IHL, as well as AL and IAL, could inhibit TNF-α-induced activation of NF-κB and MAPK pathways in b. End3 cells, suppress the expressions of MMP-3, MCP-1, and IL-1 in TNF-α-stimulated synovial fibroblasts, and IL-1, IL-6, and iNOS in LPS-activated RAW 264.7 cells in a dose-dependent manner in the range of 0.6-2.4μg/mL. Oral administration of TSL-IHL at 12.5-50mg/kg could dose-dependently alleviate the arthritic severity and paw swelling in either developing or developed phases of arthritis of rats induced by adjuvant or collagen CONCLUSIONS: These results indicated potentials of TSL-IHL in prevention and therapy of rheumatoid arthritis.


Neural correlates of motion-induced blindness in the human brain.
Motion-induced blindness (MIB) is a visual phenomenon in which highly salient visual targets spontaneously disappear from visual awareness (and subsequently reappear) when superimposed on a moving background of distracters. Such fluctuations in awareness of the targets, although they remain physically present, provide an ideal paradigm to study the neural correlates of visual awareness. Existing behavioral data on MIB are consistent both with a role for structures early in visual processing and with involvement of high-level visual processes. To further investigate this issue, we used high field functional MRI to investigate signals in human low-level visual cortex and motion-sensitive area V5/MT while participants reported disappearance and reappearance of an MIB target. Surprisingly, perceptual invisibility of the target was coupled to an increase in activity in low-level visual cortex plus area V5/MT compared with when the target was visible. This increase was largest in retinotopic regions representing the target location. One possibility is that our findings result from an active process of completion of the field of distracters that acts locally in the visual cortex, coupled to a more global process that facilitates invisibility in general visual cortex. Our findings show that the earliest anatomical stages of human visual cortical processing are implicated in MIB, as with other forms of bistable perception.